Tablets made from a composition of levodopa and carbidopa are commonly used for treating Parkinson's disease. Carbidopa is an aromatic L-amino acid decarboxylase inhibitor, which can efficiently reduce the transformation of levodopa to dopamine and raise the concentration of levodopa and dopamine that function in the brain. This kind of medicine is commercially available in nowadays, for instance: Sinemet® sold by Bristol-Myers Squibb, Parcopa® sold by Schwarz Pharma and etc.
Besides, U.S. Pat. No. 5,446,194 also discloses a medicine, entacapone, for Parkinson's disease treatment. The medicine is a catechol-O-methyl transferase (COMT) inhibitor, which is used with levodopa to raise the concentration of levodopa in the brain and increase the bioavailability of levodopa by preventing levodopa from being metabolized to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD). Comtan® produced by Orion is such kind of medicine.
Patients can take a tablet comprising levodopa and carbidopa as well as a tablet containing entacapone several times a day to control their symptoms. However, it is a burden to patients with the symptom of dysphagia or tremor to take two tablets each time.
Thus, WO 01/01984 discloses a pharmaceutical composition comprising levodopa, carbidopa and entacapone, wherein carbidopa is not mixed with levodopa and entacapone substantially to increase the bioavailability of carbidopa. The composition can improve the compliance of patients by incorporating the three ingredients in one tablet. Currently, such combination is commercially available under the trade name Stalevo®, which is co-developed by Novartis and Orion.
To tailor treatment approaches for patients, Stalevo® is provided with various dosage strengths, such as Stalevo® 50, 75, 100, 125, 150 and 200. In all the dosage forms, entacapone is in a fixed amount of 200 mg, but the amount of carbidopa/levodopa is 12.5/50 mg, 18.75/75 mg, 25/100 mg, 31.25/125 mg, 37.5/150 mg and 50/200 mg, respectively. However, it is a very complicated process to manufacture various dosage forms with the disclosure of WO 01/01984. It is the reason that carbidopa is separated from levodopa and entacapone substantially according to WO 01/01984, it has to be granulated independently. On the other hand, levodopa and entacapone can be mixed for granulating; even so, it is still a complicated process to granulate the mixtures of the two ingredients because entacapone is in a fixed amount of 200 mg in all the dosage strengths, and the weight ratio of levodopa and entacapone is different in various dosage forms. Therefore, the processes to granulate the mixture of levodopa and entacaponc have to be individually carried out for different dosage forms.